CN103880817B - A kind of chemical synthesis process of the chloro- 5- of 3- (3 '-N-Boc- pyrrole radicals) pyridine - Google Patents

Abstract

The invention relates to a chemical synthesis method of 3-chloro-5-(3'-N-Boc-pyrrolyl)pyridine. The present invention uses 3-chloro-5-pyridine formaldehyde as a raw material, and simply synthesizes 3-chloro-5-(3'-N-Boc-pyrrolyl)pyridine through five-step reactions, and provides a highly efficient compound for the synthesis of the compound synthetic method. The main steps are as follows: (A) 3-chloro-5-pyridine carboxaldehyde, methoxylmethylphosphorylide and sodium hydride are added in tetrahydrofuran or toluene solvent, and the reaction temperature is controlled to synthesize 3-(5'-chloropyridyl ) methyl acrylate; reaction to synthesize 3-(5'-chloropyridyl)-4-methyl nitrobutyrate; preparation of 4-[3-(5'-chloropyridyl)] valerolactam; reaction to obtain 3- Chloro-5-(3'-pyrrolyl)pyridine; add 3-chloro-5-(3'-pyrrolyl)pyridine and Boc anhydride to a mixed solvent of tetrahydrofuran and water or acetone and water, and add alkali sodium hydroxide Or potassium hydroxide, the reaction gives 3-chloro-5-(3'-N-Boc-pyrrolyl)pyridine.

Description

A kind of chemical synthesis method of 3-chloro-5-(3'-N-Boc-pyrrolyl)pyridine

technical field

The invention relates to a chemical synthesis method of 3-chloro-5-(3'-N-Boc-pyrrolyl)pyridine.

Background technique

Pyrrole derivatives are an important class of five-membered nitrogen heterocyclic compounds, which widely exist in the whole nature and often have important physiological and pharmacological activities. For example, pyrrole derivatives are involved in the growth, development, energy conversion and transmission of various information among organisms, death, decay and other processes. Therefore, it is of great significance to study the synthesis of pyrrole compounds.

3-Chloro-5-(3'-N-Boc-pyrrolyl)pyridine, as an important pyrrole derivative, is in great demand in cardiovascular and anticancer drugs, so the synthesis of this compound has important practical significance.

Contents of the invention

The purpose of this invention is: provide a kind of efficient chemical synthesis method of 3-chloro-5-(3'-N-Boc-pyrrolyl)pyridine.

Technical scheme of the present invention is as follows:

A kind of chemical synthesis method of 3-chloro-5-(3'-N-Boc-pyrrolyl)pyridine, it is characterized in that, take 3-chloro-5-pyridine formaldehyde as raw material, synthesized 3-chloro -5-(3'-pyrrolyl)pyridine, the synthetic route is as follows:

Described chemical synthesis method is:

(A) Add 3-chloro-5-pyridinecarbaldehyde, methoxymethylphosphorylide and sodium hydride to tetrahydrofuran or toluene solvent, control the reaction temperature, and synthesize 3-(5'-chloropyridyl)methyl acrylate ;

(B) Add 3-(5'-chloropyridyl)methyl acrylate and 1,8-diaza[5,4,0]undec-7-ene (DBU) into nitromethane, control Reaction temperature, reaction synthesis 3-(5'-chloropyridyl)-4-nitrobutyric acid methyl ester;

(C) Dissolve 3-(5'-chloropyridyl)-4-nitrobutyric acid methyl ester in methanol or ethanol solvent, add catalyst Raney nickel, feed hydrogen, and react to prepare 4-[3-(5 '-chloropyridyl)] valerolactam;

(D) Add 4-[3-(5'-chloropyridyl)]valerolactam and lithium aluminum hydride to toluene or tetrahydrofuran solvent to react to obtain 3-chloro-5-(3'-pyrrolyl)pyridine ;

(E) Add 3-chloro-5-(3'-pyrrolyl)pyridine and Boc anhydride to a mixed solvent of tetrahydrofuran and water or acetone and water, add alkali sodium hydroxide or potassium hydroxide, and react to obtain 3-chloro -5-(3'-N-Boc-pyrrolyl)pyridine.

Further, in step A, the reaction temperature is -10-20°C.

Further, in step B, the reaction temperature is 10-60°C.

Further, in step C, the hydrogenation temperature is 10-60°C.

Further, in step D, the reaction is controlled in a reflux state.

Further, in step E, the reaction temperature is 10-60°C, and the volume ratio of the mixed solvent is 1:0.5-2.

The beneficial effects of the present invention are: the chemical synthesis method of the present invention uses 3-chloro-5-pyridinecarbaldehyde as a raw material, synthesizes tert-butyl 7-nitroindole-3-carboxylate through three-step reaction, and improves the yield , providing an efficient synthetic method for the synthesis of this compound.

Detailed ways

In order to deepen the understanding of the present invention, the present invention will be further described below in conjunction with the examples. The following examples are only used to explain the present invention, and do not constitute a limitation to the protection scope of the present invention.

Example 1

Synthesis of methyl 3-(5'-chloropyridyl)acrylate:

Add 32.0g of sodium hydride (washed with petroleum ether) and 100mL of tetrahydrofuran into a three-neck flask, control the temperature at 10°C, dissolve 78.0g of methoxymethylphosphorus ylide in 150mL of tetrahydrofuran, and slowly drop it into the reaction flask. After the addition, 50.0 g of 3-chloro-5-pyridinecarbaldehyde was dissolved in 150 mL of tetrahydrofuran, and added dropwise to the reaction system to react for 1 h. The reaction solution was poured into 500mL of ice water, distilled off tetrahydrofuran, extracted with dichloromethane (200mL×3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain 3-(5'-chloropyridyl) Methyl acrylate 66.7g (95.6%).

Synthesis of 3-(5'-chloropyridyl)-4-nitrobutyric acid methyl ester:

Add 65.0g of 3-(5'-chloropyridyl)methyl acrylate and 150mL of nitromethane into a three-necked flask, and dropwise add 1,8-diaza[5,4,0]undec-7-ene ( DBU) 10.0g, react at 30°C. After the reaction, the solvent was distilled off, and recrystallized from ethanol to obtain 67.4 g (79.2%) of methyl 3-(5'-chloropyridyl)-4-nitrobutyrate.

Synthesis of 4-[3-(5'-chloropyridyl)]valerolactam:

Add 400 mL of methanol, 65.0 g of methyl 3-(5'-chloropyridyl)-4-nitrobutyrate, and 15.0 g of radium nickel into a three-necked flask, and perform hydrogenation reaction at 30°C. After the reaction was completed, filter, add 1 g of sodium methoxide to the filtrate, and stir for 1 h. Concentrate, add 200mL of dichloromethane, wash with sodium bicarbonate, wash with water, wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate to obtain 40.7g (82.4% ).

Synthesis of 3-chloro-5-(3'-pyrrolyl)pyridine:

Add 20.0 g of lithium aluminum hydride, 40.0 g of 4-[3-(5'-chloropyridyl)]valerolactam in 150 mL of tetrahydrofuran, and slowly drop them into the reaction flask. After the addition, the reaction was carried out under reflux for 1h. Filter, evaporate tetrahydrofuran, add 200 mL of dichloromethane, wash with saturated sodium bicarbonate, wash with water, wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate to obtain 34.8 g of 3-chloro-5-(3'-pyrrolyl)pyridine ( 93.7%).

Synthesis of 3-chloro-5-(3'-N-Boc-pyrrolyl)pyridine:

Add 200mL of tetrahydrofuran and 200mL of water into a three-necked flask, then add 32.0g of 3-chloro-5-(3'-pyrrolyl)pyridine, 40.0g of Boc anhydride and 7.8g of sodium hydroxide, and react at 20°C for 2h. Evaporate tetrahydrofuran, add 200mL of water, extract with dichloromethane (100mL×3), wash with saturated sodium bicarbonate, wash with water, wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate to obtain 3-chloro-5-(3'-N -Boc-pyrrolyl)pyridine 48.5 g (97.9%).

Example 2

Synthesis of methyl 3-(5'-chloropyridyl)acrylate:

Add 32.0g of sodium hydride (washed with petroleum ether) and 100mL of toluene into the three-necked flask, control the temperature at 10°C, dissolve 78.0g of methoxyacylmethylphosphorus ylide in 150mL of toluene, and slowly drop it into the reaction flask. After the addition, 50.0 g of 3-chloro-5-pyridinecarbaldehyde was dissolved in 150 mL of toluene, and added dropwise to the reaction system to react for 1 h. The reaction solution was poured into 500mL of ice water, the toluene was distilled off, and extracted with dichloromethane (200mL×3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain 3-(5'-chloropyridyl) Methyl acrylate 65.4 g (93.7%).

Synthesis of 3-(5'-chloropyridyl)-4-nitrobutyric acid methyl ester:

Add 65.0g of 3-(5'-chloropyridyl)methyl acrylate and 150mL of nitromethane into a three-necked flask, and dropwise add 1,8-diaza[5,4,0]undec-7-ene ( DBU) 10.0g, react at 20°C. After the reaction, the solvent was distilled off and recrystallized from ethanol to obtain 67.7 g (79.6%) of methyl 3-(5'-chloropyridyl)-4-nitrobutyrate.

Synthesis of 4-[3-(5'-chloropyridyl)]valerolactam:

Add 400 mL of ethanol, 65.0 g of methyl 3-(5'-chloropyridyl)-4-nitrobutyrate and 15.0 g of radium nickel into a three-necked flask, and perform hydrogenation reaction at 30°C. After the reaction was completed, filter, add 1 g of sodium methoxide to the filtrate, and stir for 1 h. Concentrate, add 200mL of dichloromethane, wash with sodium bicarbonate, wash with water, wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate to obtain 41.4g (83.8% ).

Synthesis of 3-chloro-5-(3'-pyrrolyl)pyridine:

Add 20.0 g of lithium aluminum hydride, 40.0 g of 4-[3-(5'-chloropyridyl)]valerolactam in 150 mL of toluene, and slowly drop them into the reaction flask. After the addition, the reaction was carried out under reflux for 1h. Filter, distill off toluene, add 200 mL of dichloromethane, wash with saturated sodium bicarbonate, wash with water, wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate to obtain 32.5 g of 3-chloro-5-(3'-pyrrolyl)pyridine ( 87.5%).

Synthesis of 3-chloro-5-(3'-N-Boc-pyrrolyl)pyridine:

Add 200mL of tetrahydrofuran and 200mL of water into a three-necked flask, then add 32.0g of 3-chloro-5-(3'-pyrrolyl)pyridine, 40.0g of Boc anhydride and 10.0g of potassium hydroxide, and react at 20°C for 2h. Evaporate tetrahydrofuran, add 200mL of water, extract with dichloromethane (100mL×3), wash with saturated sodium bicarbonate, wash with water, wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate to obtain 3-chloro-5-(3'-N -Boc-pyrrolyl)pyridine 48.7 g (98.3%).

Example 3

Synthesis of methyl 3-(5'-chloropyridyl)acrylate:

Add 32.0g of sodium hydride (washed with petroleum ether) and 100mL of tetrahydrofuran into a three-necked flask, control the temperature at 0°C, dissolve 78.0g of methoxylmethylphosphonium ylide in 150mL of tetrahydrofuran, and slowly drop it into the reaction flask. After the addition, 50.0 g of 3-chloro-5-pyridinecarbaldehyde was dissolved in 150 mL of tetrahydrofuran, and added dropwise to the reaction system to react for 1 h. The reaction solution was poured into 500mL of ice water, distilled off tetrahydrofuran, extracted with dichloromethane (200mL×3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain 3-(5'-chloropyridyl) Methyl acrylate 66.1 g (94.7%).

Synthesis of 3-(5'-chloropyridyl)-4-nitrobutyric acid methyl ester:

Add 65.0g of 3-(5'-chloropyridyl)methyl acrylate and 150mL of nitromethane into a three-necked flask, and dropwise add 1,8-diaza[5,4,0]undec-7-ene ( DBU) 10.0g, react at 10°C. After the reaction, the solvent was distilled off, and recrystallized from ethanol to obtain 65.2 g (76.6%) of methyl 3-(5'-chloropyridyl)-4-nitrobutyrate.

Synthesis of 4-[3-(5'-chloropyridyl)]valerolactam:

Add 400 mL of methanol, 65.0 g of methyl 3-(5'-chloropyridyl)-4-nitrobutyrate and 15.0 g of radium nickel into a three-neck flask, and perform hydrogenation reaction at 20°C. After the reaction was completed, filter, add 1 g of sodium methoxide to the filtrate, and stir for 1 h. Concentrate, add 200mL of dichloromethane, wash with sodium bicarbonate, wash with water, wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate to obtain 41.2g (83.4% ).

Synthesis of 3-chloro-5-(3'-pyrrolyl)pyridine:

Add 20.0 g of lithium aluminum hydride, 40.0 g of 4-[3-(5'-chloropyridyl)]valerolactam in 200 mL of tetrahydrofuran, and slowly drop them into the reaction flask. After the addition, the reaction was carried out under reflux for 1h. Filter, evaporate tetrahydrofuran, add 200 mL of dichloromethane, wash with saturated sodium bicarbonate, wash with water, wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate to obtain 33.5 g of 3-chloro-5-(3'-pyrrolyl)pyridine ( 90.2%).

Synthesis of 3-chloro-5-(3'-N-Boc-pyrrolyl)pyridine:

Add 150mL of tetrahydrofuran and 250mL of water into a three-necked flask, then add 32.0g of 3-chloro-5-(3'-pyrrolyl)pyridine, 40.0g of Boc anhydride and 7.8g of sodium hydroxide, and react at 20°C for 2h. Evaporate tetrahydrofuran, add 200mL of water, extract with dichloromethane (100mL×3), wash with saturated sodium bicarbonate, wash with water, wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate to obtain 3-chloro-5-(3'-N -Boc-pyrrolyl)pyridine 46.2 g (93.3%).

Claims (1)

1. a kind of chemical synthesis process of the chloro- 5- of 3- (3 '-N-Boc- pyrrole radicals) pyridine, which is characterized in that with the chloro- 5- pyridine of 3- Formaldehyde is raw material, has synthesized the chloro- 5- of 3- (3 '-pyrrole radicals) pyridine through the reaction of five steps, synthetic route is as follows:

The chemical synthesis process are as follows:

(A) it by the chloro- 5- pyridine carboxaldehyde of 3-, methoxy acyl methyl phosphorus ylide and sodium hydride, is added in tetrahydrofuran or toluene solvant, Reaction temperature is controlled, 3- (5 '-chloropyridine base) methyl acrylate has been synthesized；Reaction temperature is -10-20 DEG C；

(B) by 3- (5 '-chloropyridine base) methyl acrylate and 1, nitre is added in 11 carbon -7- alkene (DBU) of 8- diaza [5,4,0] In methylmethane, reaction temperature, reaction synthesis 3- (5 '-chloropyridine base) -4- nitro butyric acid methyl ester are controlled；Reaction temperature is 10-60 ℃；

(C) 3- (5 '-chloropyridine base) -4- nitro butyric acid methyl ester is dissolved in methanol or alcohol solvent, catalyst raney nickel is added, It is passed through hydrogen, reaction preparation 4- [3- (5 '-chloropyridine base)] valerolactam；Hydrogenation temperature is 10-60 DEG C

(D) it by 4- [3- (5 '-chloropyridine base)] valerolactam and lithium aluminium hydride reduction, is added in toluene or tetrahydrofuran solvent, instead It should obtain the chloro- 5- of 3- (3 '-pyrrole radicals) pyridine；Reaction controlling is in reflux state；

(E) by the chloro- 5- of 3- (3 '-pyrrole radicals) pyridine and Boc acid anhydrides, the mixed solvent of tetrahydrofuran and water or acetone and water is added In, alkali sodium hydroxide or potassium hydroxide is added, reaction obtains the chloro- 5- of 3- (3 '-N-Boc- pyrrole radicals) pyridine, and reaction temperature is 10-60 DEG C, the volume ratio of mixed solvent is 1:0.5-2.